Serum Toxicity Markers Research Articles

Unlocking apoptosis in triple negative breast cancer: Harnessing “glutamine trap” to amplify the efficacy of lapatinib-loaded mixed micelles

Certain aggressive cancers, such as triple-negative breast cancer (TNBC), heavily bank on glutamine for their proliferation and survival. In this context, TNBC functions as a “glutamine trap,” extracting circulating glutamine at a rate surpassing that of any other organ. Moreover, the overexpression of Alanine, Serine, Cysteine Transporter 2 (ASCT2), a key player in glutamine uptake, further underscores the significance of targeted therapy to enhance TNBC treatment. This led to the exploration of a novel approach involving hydrophobized Pluronic-based mixed micelles achieved through the use of docosahexaenoic acid and stapled with glutamine for displaying inherent ASCT2 targeting ability—a formulation termed LPT G-MM. LPT G-MM exhibited optimal characteristics, including a size of 163.66 ± 10.34 nm, a polydispersity index of 0.237 ± 0.083, and an enhanced drug loading capacity of approximately 15 %. Transmission electron microscopy validated the spherical shape of these micelles. In vitro release studies demonstrated drug release in a sustained manner without the risk of hemolysis. Importantly, LPT G-MM displayed heightened cellular uptake, increased cytotoxicity, a lower IC50 value, elevated reactive oxygen species, induced mitochondrial membrane depolarization, and a greater apoptosis index in TNBC cell lines compared to free LPT. The pharmacokinetic profile of LPT G-MM revealed a substantial rise in half-life (t1/2) by approximately 1.48-fold and an elevation in the area under the curve [AUC(0→∞)] by approximately 1.19-fold. Moreover, there was a significant reduction in the percentage of tumor volume by approximately 7.26-fold, along with decreased serum toxicity markers compared to free LPT. In summary, LPT G-MM demonstrated promising potential in boosting payload capacities and targeting specificity in the context of TNBC treatment.

Beneficial effects of Chrysin on Cadmium‐induced nephrotoxicity in rats: Modulating the levels of Nrf2/HO‐1, RAGE/NLRP3, and Caspase-3/Bax/Bcl-2 signaling pathways

Cadmium (Cd) is a toxic heavy metal that targets the kidney directly in the body. Chrysin (CHR) is a natural flavonoid with many properties such as antioxidant, anti-inflammatory and anti-apoptotic. The current study discloses new evidence as regards of the curative effects of CHR on Cd-induced nephrotoxicity by regulating oxidative stress, apoptosis, autophagy, and inflammation. Cd was administered orally at a dose of 25 mg/kg body weight alone or in combination with orally administered CHR (25 and 50 mg/kg body weight) for 7 days. Biochemical, molecular, and histological methods were used to investigate inflammation, apoptosis, autophagy, and oxidant pathways in renal tissue. Renal function tests were also evaluated. Cd caused an increase in serum toxicity markers, lipid peroxidation and a decrease in the activities of antioxidant enzymes. Nrf-2 triggered inflammatory responses by suppressing HO-1 and NQO1 mRNA transcripts and increasing NF-κB, TNF-α, IL-1β and iNOS mRNA transcripts. Cd caused inflammasome by increasing RAGE and NLRP3 mRNA transcripts. In addition, Cd application caused apoptosis by increasing Bax, Apaf-1 and Caspase-3 mRNA transcripts and decreasing Bcl-2 mRNA transcript level. It caused autophagy by increasing the activity of Beclin-1 level. CHR treatment had the opposite effect on all these values and reduced the damage caused by all these signal pathways. Overall, the data of this study indicate that renal damage associated with Cd toxicity could be ameliorated by CHR administration.

Green Synthesis of Silver Nanoparticles Using Spilanthes acmella Leaf Extract and its Antioxidant-Mediated Ameliorative Activity against Doxorubicin-Induced Toxicity in Dalton's Lymphoma Ascites (DLA)-Bearing Mice.

Green synthesis of metal nanoparticles is a rapidly growing research area in the field of nanotechnology because of their biomedical applications. This study describes the synthesis of silver nanoparticles (AgNPs) using Spilanthes acmella leaf extract and its ameliorative effects against doxorubicin-induced toxicity. The formation of AgNPs was confirmed by a ultraviolet-visible (UV-vis) spectrum that revealed an absorption band at 430 nm. A shift in the absorption bands in Fourier-transform infrared spectroscopy (FT-IR) confirmed the bioactive molecules of S. acmella leaf extract that acted as a reducing and capping agent. The spherical shape of AgNPs was confirmed by scanning electron microscope (SEM) analysis, and the presence of elemental silver was indicated by energy dispersive X-ray spectroscopy (EDS) analysis. X-ray diffraction (XRD) analysis revealed that the crystalline size of the synthesized AgNPs was 6.702 nm. Treatment of Dalton's lymphoma ascites (DLA) mice with 20 mg/kg of doxorubicin (DOX) significantly increased the activities of serum toxicity markers including aspartate amino-transferase (AST), alanine amino-transferase (ALT), and lactate dehydrogenase (LDH). However, compared to DOX alone treatment, the coadministration of DOX and AgNPs reduced AST, ALT, and LDH activities. DOX alone treatment reduced glutathione (GSH) contents and decreased the activities of glutathione-s-transferase (GST) and superoxide dismutase (SOD) in DLA mice. However, the administration of AgNPs to DOX-treated DLA mice increased GSH content and the activities of GST and SOD. Consistently, biosynthesized AgNPs were found to possess significantly higher free-radical scavenging activities when compared to the S. acmella leaf extract, as measured by ABTS, DPPH, and O2 •- assays. The biosynthesized AgNPs also showed significant inhibitory activities against erythrocyte hemolysis and lipid peroxidation in the liver homogenate.

Hypolipidemic and antioxidant effects of vegetal milk produced with Mucuna pruriens L. seed in rats fed a high-fat diet

Research on the production of lipid-lowering drugs from natural sources has become increasingly important. In this study, we investigated the hypolidemic properties of the vegetable milk produced from the seeds of Mucuna pruriens L. Vegetable milk were produced from whole or dehulled seeds of two varieties of M. pruriens, var. Veracruz: dehulled Veracruz milk (DVM) and whole Veracruz milk (WVM); and var. Cochinchinensis: dehulled Cochinchinensis milk (DCM) and whole Cochinchinensis milk (WCM). Then, the phenolic and antioxidant properties of these milks were analyzed. Furthermore, the effect of the intake on selected antioxidant and serum toxicity markers was assessed on hyperlipidemic rats. Three controls were made of normal rats, untreated hyperlipidemic rats, and hyperlipidemic rats treated with atorvastatin (10 mg/kg/day). Four test groups were made of hyperlipidemic rats and treated for 4 weeks with a diet in which vegetable milk (DCM, WCM, DVM, and WVM) was used as the protein source instead of casein. The antioxidant activity (DPPH free radical scavenging 167.2–299.9 mg/100 ml) and phenolic compounds (122.8–199.5 mg/100 ml) were higher in milks produced with whole seeds than in milks produced with dehulled seeds. Moreover, the levels of creatinine, ALAT, ASAT, and MDA, as well as total, LDL, and VLDL cholesterol, significantly increased in the serum of hyperlipidemic rats (p < 0.05). However, the antioxidant enzyme activities of treated rats significantly (p < 0.05) decreased compared to those of normal rats. The intake of M. pruriens milk significantly reduced the levels of total cholesterol, triglycerides, glucose and LDL in the serum (p < 0.05). Whole M. pruriens milk exhibited higher antioxidant properties, but showed high levels of ALAT, ASAT, and creatinine, which could have an adverse effect on certain organs. Overall, dehulled M. pruriens milk could be a potent hypolipidemic and antioxidant functional food.

In vivo investigation of the inhibitory effect of Peganum harmala L. and its major alkaloids on ethylene glycol-induced urolithiasis in rats

Ethnopharmacological relevancePeganum harmala L. is a traditional medicinal plant used for centuries in folk medicine. It has a wide array of therapeutic attributes, which include hypoglycemic, sedative, anti-inflammatory, and antioxidant properties. The fruit decoction of this plant was claimed by Avicenna as traditional therapy for urolithiasis. Also, P. harmala seed showed a clinical reduction in kidney stone number and size in patients with urolithiasis. Aim of the studyIn light of the above-mentioned data, the anti-urolithiatic activities of the seed extracts and the major β-carboline alkaloids of P. harmala were investigated. Materials and methodsExtraction, isolation, and characterization of the major alkaloids were performed using different chromatographic and spectral techniques. The in vivo anti-urolithiatic action was evaluated using ethylene glycol (EG)-induced urolithiasis in rats by studying their mitigating effects on the antioxidant machinery, serum toxicity markers (i.e. nitrogenous waste, such as blood urea nitrogen, uric acid, urea, and creatinine), minerals (such as Ca, Mg, P, and oxalate), kidney injury marker 1 (KIM-1), and urinary markers (i.e. urine pH and urine output). ResultsTwo major alkaloids, harmine (P1) and harmalacidine HCl (P2), were isolated and in vivo evaluated alongside the different extracts. The results showed that P. harmala and its constituents/fractions significantly reduced oxidative stress at 50 mg/kg body weight, p.o., as demonstrated by increased levels of glutathione (GSH), glutathione reductase (GR), glutathione peroxidase (GPx), and catalase (CAT) in kidney homogenate as compared to the EG-treated group. Likewise, the total extract, pet. ether fraction, n-butanol fraction, and P1, P2 alleviated malondialdehyde (MDA) as compared to the EG-treated group. Serum toxicity markers like blood urea nitrogen (BUN), creatinine, uric acid, urea, kidney injury molecule-1 (Kim-1), calcium, magnesium, phosphate, and oxalate levels were decreased by total extract, pet. ether fraction, n-butanol fraction, P1, and P2 as compared to the EG-treated group. Inflammatory markers like NFκ-B and TNF-α were also downregulated in the kidney homogenate of treatment groups as compared to the EG-treated group. Moreover, urine output and urine pH were significantly increased in treatment groups as compared to the EG-treated group deciphering anti-urolithiatic property of P. harmala. Histopathological assessment by different staining patterns also supported the previous findings and indicated that treatment with P. harmala caused a gradual recovery in damaged glomeruli, medulla, interstitial spaces and tubules, and brown calculi materials as compared to the EG-treated group. ConclusionThe current research represents scientific evidence on the use of P. harmala and its major alkaloids as an effective therapy in the prevention and management of urolithiasis.

Lipid- and TPGS-Based Core-Shell-Type Nanocapsules Endowed with High Paclitaxel Loading and Enhanced Anticancer Potential.

The current study elucidates the improved drug loading of paclitaxel (PTX) in lipid- and D-α-tocopheryl polyethylene glycol succinate (TPGS)-based core-shell-type lipid nanocapsules (PTX-TPGS-LNC) for augmenting the therapeutic efficacy and curbing the toxicity. PTX-TPGS-LNCs were formulated by employing anti-solvent precipitation technique and displayed a particle size of 162.1 ± 4.70nm and % practical drug loading of 15.04 ± 2.44%. Electron microscopy revealed that PTX-TPGS-LNCs have spherical morphology and the inner core was surrounded by a relatively lighter region, i.e., layer of lipids and TPGS. The nature of loaded PTX inside the PTX-TPGS-LNC was also confirmed using DSC and PXRD analysis. The in vitro release study showed biphasic and sustained release pattern of PTX from PTX-TPGS-LNC and it showed ~ threefold higher PTX uptake in MCF-7 cell line in comparison to free PTX. Moreover, it was apparent from the cytotoxicity assay that PTX-TPGS-LNC displayed higher cytotoxicity in MCF-7 cells and revealed ~ 2.92-fold decrease in IC50 value as against free PTX when incubated for 72h. The apoptotic index in case of PTX-TPGS-LNC was ~ twofold higher than free PTX. The pharmacokinetic profile of PTX-TPGS-LNC revealed a ~ 3.18-fold increase in t1/2 and a ~ 2.62-fold higher AUC(0→∞) compared to Intaxel®. Finally, treatment with PTX-TPGS-LNC demonstrated significant lowering in the % tumor burden and serum toxicity markers compared to marketed formulation Intaxel®. Thus, the lipid- and TPGS-based core-shell-type LNC with high PTX loading can advance the existing standards of therapy for overshadowing cancer.

Unfolding the Potency of Adenosine in Targeting Triple Negative Breast Cancer via Paclitaxel-Incorporated pH-Responsive Stealth Liposomes.

Triple-negative breast cancer (TNBC) belongs to the category of the most destructive forms of breast cancer. Being a highly potent chemotherapeutic agent, paclitaxel (PTX) is extensively utilized in the management of various cancers. Commercially available PTX formulations contain non-targeted drug carriers that result in low antitumor activity because of non-specific tissue distribution. Thus, to resolve this issue, we designed PTX-loaded pH-sensitive liposomes (pH Lipos) in the present investigation and used adenosine (ADN) as a targeting ligand. Further, d-α-tocopheryl polyethylene glycol succinate (TPGS) was incorporated into the liposomes to impart a stealth effect to the system. For the development of these pH Lipos, different conjugates were synthesized (ADN-CHEMS and TPGS-ADN) and further utilized for the preparation of ADN-PEG-pH Lipo and ADN-pH Lipo by a thin-film hydration method. DOPE:HSPC:CHEMS:cholesterol at a molar ratio of 3:3:2:2 was selected for the preparation of pH-Lipo possessing 7.5% w/w drug loading. They showed a particle size below 140 nm, a PDI below 0.205, and a % EE greater than 60%. All of the pH Lipos displayed a biphasic pattern of PTX release at pH 7.4 and 5.5. However, the percent drug release at pH 5.5 was substantially greater because of the pH-sensitive nature of the liposomes. The MDA MB 231 and 4T1 cell lines depicted improvement in the qualitative as well as quantitative cellular uptake of PTX ADN-PEG-pH Lipo with a substantial decrease in the IC50 value. Moreover, a higher apoptotic index was observed with pH Lipo compared to free PTX. PTX ADN-PEG-pH Lipo revealed a 3.98- and 3.41-fold rise in the AUC and t1/2 values of PTX compared to Intaxel, respectively. Overall, characteristic decreases in tumor volume and serum toxicity marker levels were observed, which confirmed the development of an efficient and safe formulation.

D-limonene (5 (one-methyl-four-[1-methylethenyl]) cyclohexane) diminishes CCl4-induced cardiac toxicity by alleviating oxidative stress, inflammatory and cardiac markers

ABSTRACT Background: The cardiovascular crisis is advancing rapidly throughout the world. A large number of studies have shown that plant polyphenols affect major mechanisms involved in cardiovascular events through their action on the antioxidant system, signaling, and transcription pathways. D-limonene, a monocyclic monoterpene obtained from citrus fruits, is reported to possess many pharmacological activities. Methods: The experiment was designed to determine the protective effect of D-limonene against cardiac injury induced by CCl4 in Wistar rats. Rats were treated with two doses of D-limonene against cardiac injury induced by CCl4. Serum toxicity markers, cardiac toxicity biomarker enzymes, inflammatory mediators, anti-oxidant armory, lipid peroxidation, lipid profile, and histology were done. Results: CCl4 intoxication resulted in a substantial rise in FFA, TC, TG, PL, LDL, VLDL, and a reduction in HDL, restoring these changes with the administration of D-limonene at a dosage of 200 mg/kg. CCl4 administration also resulted in lipid oxidation and decreased antioxidant activity. At the same time, D-limonene at a dosage of 200 mg/kg body weight inhibited LPO and restored in vivo antioxidant components to normal. CCl 4 intoxication also resulted in a significant increase in inflammatory markers like IL-6, TNF-α, high sensitivity Corticotropin Releasing Factor (Hs-CRF), and biomarkers of cardiac toxicity like alanine aminotransferase (ALT), lactate dehydrogenase (LDH), creatine kinase (CK), creatine kinase MB (CKMB), and Troponin I & troponin-t activities. D-limonene reversed all these changes to normal. Histology further confirmed our obtained results. Conclusion: These findings indicate that D-limonene can ameliorate cardiac injury at a 200 mg/kg body weight dosage. Henceforth, D-Limonene intervenes in mediating CCl4 induced toxicity by various signaling pathways.

Measuring Serum Toxicity Markers to Evaluate the Safety of Commercially Available Spirulina Products in Mice

Spirulina a multicellular, blue-green alga has drawn attention as a viable food supplement due to its suitable nutrient composition, however, there is a dearth of information regarding its safety. This study aimed to measure the heavy metal concentrations in commercially available Spirulina products and evaluate the safety using the in vivo method. A total of 54 mice were randomly divided into three groups; Group 1 (n = 18) served as a control and received a basal diet. Group 2 (n = 20) served as a test and received Spirulina powder (15%) blended with a basal diet. Group 3 (n = 16) serves as a standard and received a basal diet supplemented with nutritional supplements. The findings showed that the concentration of serum aspartate aminotransferase, alanine aminotransferase, cystatin C, and troponin I after consuming the experimental diets was not statistically different between groups (p &gt; 0.05). The concentrations of mercury (0.000036 mg/kg), lead (0.0047 mg/kg), cadmium (0.00048 mg/kg), and arsenic (0.0046 mg/kg) was very little to cause toxic effect and the levels were below the European Communities Commission (EC) recommended maximum heavy metal levels in foodstuffs. Therefore, consumption of Spirulina at a proportion of 15% does not exert any hepatic, renal, and cardiac toxicities in the mice. However, evaluating the safety of higher doses (&gt; 15%) is required.

Toxicological effect of Artemisinin-Based Combination Therapies plus Paracetamol in malaria patients.

Following the paucity of safety reports in the use of Artemisinin-Based Combination Therapies (ACTs) plus paracetamol, the study assessed safety potential of artemether-lumefantrine (ALP), artesunate-amodiaquine (AAP), artesunate-mefloquine (AMP), artesunate-sulphadoxine-pyrimethamine (ASPP) and dihydroartemisinin-piperaquine (DHPP) combination with paracetamol in malaria patients. ACTs and paracetamol were administered concomitantly in conventional doses/regimen to randomly selected patients. Blood samples were collected from the ante-cubital vein before and after completion of therapies. Toxicity markers such as weights, glucose, lipids, renal electrolytes, liver enzymes and haematological indices were assessed using standard protocols. The total numbers of participants were 57 patients. Male to female ratio was 1:1.1. Mean body weight and ages were 59.19 ± 1.39 kg and 42.86 ± 1.32 years respectively. The mean temperatures prior to and after therapy were 37.49 ± 1.02 °C and 37.50 ± 0.17 °C respectively. Mean parasitaemia before the commencement of therapy was 6282 ± 21.01 parasites/μl. Out of thirty-seven toxicological indices evaluated, twenty-four were significantly altered by ACTs plus paracetamol (P < 0.05). Increased serum toxicity markers due to the drug combinations were glucose (AAP, AMP), urea (ALP, ASPP), bicarbonate ion (ALP, AAP, AMP, ASPP), chloride ion (ALP, AAP, AMP), creatinine (ALP, AAP, AMP, ASPP), alkaline phosphatase (ALP, AAP), aspartate aminotransferase and alanine aminotransferase (ALP, AAP, AMP, ASPP, DHPP), total protein (AMP, DHPP) and albumin (AMP, DHPP). Decreased serum toxicity markers due to the drugs were glucose (ALP, ASPP, DHPP), urea (AMP), bicarbonate ion (DHPP), chloride ion (ASPP, DHPP), creatinine (DHPP), alkaline phosphatase (AMP, ASPP, DHPP), total protein (ALP, AAP, and ASPP) and albumin (ALP, AAP, ASPP). Altered haematological indices were white blood cells, red blood cells, mean cell haemoglobin and platelets. Since ACTs plus paracetamol altered human system, discrete selection is essential in managing uncomplicated malaria most especially in patients with co-morbid conditions.

Lipid and Biosurfactant Based Core–Shell-Type Nanocapsules Having High Drug Loading of Paclitaxel for Improved Breast Cancer Therapy

The current investigation illustrates high drug loading of Paclitaxel (PTX) in lipid- and biosurfactant-based core-shell-type nanocapsules for improving therapeutic potential and reducing toxicity of PTX. The nanocapsules were prepared using the antisolvent precipitation technique having a particle size of 253.8 ± 15.4 nm and drug loading of ∼19%. The microscopic evaluation revealed the spherical shape of the nanocapsules and corroborated with the particle size obtained from Zetasizer. It also revealed the drug core enveloped by the relatively lighter shadowed region, that is, the layer of lipids and the biosurfactant. The in vitro release study showed biphasic and sustained release pattern of PTX from core-shell-type nanocapsules. In case of nanocapsules, the cellular uptake in the MCF-7 cell line was augmented ∼3.17-fold as compared to free PTX. Further, it was evident from the cytotoxicity assay that nanocapsules displayed greater cytotoxicity in MCF-7 cells and ∼2.98-fold decrease in the IC50 value as compared to free PTX. The apoptotic index observed in case of nanocapsules was ∼2.04-fold higher than that of free PTX. Furthermore, the pharmacokinetic profile of nanocapsules revealed a ∼7.21-fold increase in t1/2 and a ∼3.27-fold higher AUC(0→∞) compared to Intaxel. Finally, treatment with PTX core-shell-type nanocapsules demonstrated significant cutback in the % tumor burden and serum toxicity markers compared to marketed formulation. Thus, the current approach of core-shell-type nanocapsules with high drug loading can improve the current standards of PTX therapy for treatment of cancer.

Evaluation of the protective effects of Ganoderma applanatum against doxorubicin-induced toxicity in Dalton’s Lymphoma Ascites (DLA) bearing mice

The toxic side effects of doxorubicin in cancer treatment are well established. Here we show that methanolic extract of the fungus Ganoderma applanatum offers protection against cardio- and hepatotoxicity induced by doxorubicin (DOX) in Dalton’s Lymphoma Ascites (DLA) bearing mice. Treatment of DLA mice with 20 mg/kg of doxorubicin significantly increased the activities of serum toxicity markers including aspartate amino-transferase (AST), alanine amino-transferase (ALT) and lactate dehydrogenase (LDH). However, co-administration of doxorubicin (20 mg/kg) by intraperitoneal injection and G. applanatum (150 mg/kg) by oral gavage in DLA mice lowered the AST, ALT, and LDH activities when compared to DOX alone treatment. Treatment of DLA mice with DOX alone resulted in reduced GSH contents, and decreased the activities of glutathione-s-transferase (GST), catalase (CAT), and superoxide dismutase (SOD). Treatment of DOX-administered DLA mice with G. applanatum however increased the GSH content and elevated the activities of GST, CAT, and SOD. Among the various solvent extracts of G. applanatum, methanolic extract showed the highest phenolic (376.5 ± 15.24 mg GAE/g) and flavonoid (4717.79 ± 170.22 mg quercetin/g) contents compared to the aqueous (216.3 ± 7.33 mg GAE/g) and chloroform extracts (137.27 ± 1.03 mg GAE/g). Consistently, the methanolic extract was found to possess the highest free radical scavenging activities when compared to the aqueous and chloroform extracts as measured by ABTS and DPPH assays. Our results thus suggest that the protective roles of G. applanatum in DOX-induced toxicity could be an attribute of the antioxidant properties conferred by the high phenolic and flavonoid contents.

Hepatic &amp; Renal Toxicity of Energy Drinks, a Serious Health Risk, Wistar Albino Rats Study

The recent years have seen a significant increase in the individual consumption of energy drinks across the globe. As a result, notable concerns continue to rise both among the public and among the scientific community, concerning the health effects that energy drinks pose to individuals. This study therefore examines the adverse effects of energy drinks on health, using ten normal albino rats as specimens. The specimen was then divided into two groups consisting of five rats each, with one group was given energy drinks while the control group was given normal drinking water days for a period of 21 days. The specimen was then sacrificed and their blood samples used for biochemical and histological studies. The study findings reveal that energy drink consumption significantly increased the serum aspartate amino transferase (AST), alanine amino transferase (ALT), urea and creatinine levels when compared with the control group. In addition, the study demonstrates that energy drink consumption significantly decreased body weight and organ to body weight ratios when compared with the control group. The study further recognizes that the consumption of energy drink is associated with significant alterations in serum toxicity markers, bodyweight, organ body weight and histopathological changes. The study therefore recommends that need for public health education to educate individuals; especially youths about the risks of consuming highly caffeinated energy drinks. The study also recommends the need for further studies in order to minimize the harm excess and long-term consumption of energy drinks presented to the public.

Antioxidant and anti-apoptotic effects of vitexilactone on cisplatin-induced nephrotoxicity in rats

ABSTRACTCisplatin (CP) is an antineoplastic drug; however, owing to its nephrotoxicity, its clinical use is limited. We investigated whether vitexilactone (vitex) is a safe and effective treatment for CP induced kidney injury. We allocated Sprague-Dawley rats into six groups: control group, low dose-high dose vitex groups (40 and 80 mg/kg vitex for 6 days before administration of CP), CP group (single 6 mg/kg dose on day 6) and CP + low dose vitex-CP + high dose vitex group (40 and 80 mg/kg vitex for 6 days, and a single 6 mg/kg dose of CP on day 6. Rats were euthanized 5 days after CP treatment. After exposure to CP and/or vitex, total oxidative stress and total antioxidant status were assessed. The histology of the kidney was examined using hematoxylin and eosin, and periodic acid-Schiff. We used immunohistochemical and fluorescence staining to detect expression of caspase-3. We also measured blood urea nitrogen, uric acid and creatinine levels. Nephroprotective effects of vitex were associated with decreased serum toxicity markers and increased antioxidant activity. Vitex also reduced the expression of the apoptosis marker, caspase-3. Treatment with CP increased blood urea nitrogen, uric acid, creatinine levels and total antioxidant status, and decreased total antioxidant status compared to the control group. Use of vitex for protection from CP induced nephrotoxicity appears to be a safe and efficacious alternative for treatment of kidney injury.

Moringa oleifera seed oil modulates redox imbalance and iNOS/NF-κB/caspase-3 signaling pathway to exert antioxidant, anti-inflammatory and antiapoptotic mechanisms against anticancer drug 5-fluorouracil-induced nephrotoxicity in rats

5-Fluorouracil (5-FU) is a strong anticancer agent commonly used for the treatment of various malignancies. However, its clinical utility is countered by non-targeted nephrotoxicity and hepatotoxicity which is sometimes unbearable for cancer patients. Accumulating evidence has implicated oxidative stress and pro-inflammation in 5-FU toxicity. The study explored whether Moringa oleifera seed oil (MOO) could protect against 5-FU-induced nephrotoxicity and its mechanism of action in Wistar rats. Rats were subjected to prophylactic oral treatment of MOO (5 ml/kg body weight/day) for 10 days against nephrotoxicity induced by intraperitoneal administration of 5-FU (75 mg/kg bw) on day 8 and 9, and were sacrificed after 48 h. The possible mechanism of 5-FU-induced renal toxicity is the renal induction of oxidative stress, pro-inflammation via overexpression of renal inducible nitric oxide synthase/nuclear factor-κB and cytokines and activation of apoptotic pathway by upregulation of caspase-3. However, prophylactic treatment with MOO prominently decreased serum toxicity markers, markedly increased antioxidant defense mechanism accompanied with anti-inflammatory and antiapoptotic effects in the kidney. Changes in the histopathology confirmed the biochemical findings. Our findings suggest 5-FU-induced nephrotoxicity by oxidative stress, exacerbation of pro-inflammation and apoptosis. The inhibition of the alterations by MOO is relevant in the clinical management of 5-FU nephrotoxicity in cancer patients.

Water Extract of Acori Graminei Rhizoma Attenuates Features of Rheumatoid Arthritis in DBA/1 Mice.

The dry rhizome of Acorus gramineus Solander, known as Acori Graminei Rhizoma, is used to treat dementia, stroke, eczema, and indigestion in traditional Chinese medicine, traditional Korean medicine, and traditional Japanese Kampo medicine. Previous studies have reported that Acori Graminei Rhizoma extract ameliorated cognitive impairment in Aβ1-42 injected mice. However, the effect of Acori Graminei Rhizoma on type II collagen induced arthritis (CIA) has not been elucidated. Thus, we evaluated the water extract of Acori Graminei Rhizoma (WAG) in CIA mice models. Male DBA/1 mice were separated into five groups (NOR; n=10, CON; n=10, CIA + methotrexate (MTX); n=10, CIA + 100 mg/kg WAG; n=10, CIA + 500 mg/kg WAG; n=10). CIA was induced by injecting the mice with bovine type II collagen, after which the mice were treated with WAG and/or MTX. Hematological parameters and liver and kidney serum toxicity markers were analyzed. Further, serum levels of interleukin (IL)-6, TNF-α, and type II collagen IgG were analyzed via enzyme-linked immunosorbent assay (ELISA). Treatment with 500 mg/kg WAG decreased serum levels of IL-6, TNF-α, and collagen IgG in a CIA model. Moreover, WAG treatment decreased CIA-induced swelling of mouse hind legs, infiltration of inflammatory cells into the synovial membrane, and blood neutrophil levels. WAG administration did not influence hematological parameters or kidneys and liver toxicity markers. WAG may be used to treat arthritis by reducing the inflammation indicators. However, further experiments are required to determine how WAG affects inflammation mechanisms in vitro and in vivo.

Novel biosurfactant and lipid core-shell type nanocapsular sustained release system for intravenous application of methotrexate

In an attempt to prepare novel core shell nanocapsules, lipid and Stearic acid-Valine conjugate (Biosurfactant) based nanosystem was prepared to attain high drug loading of hydrophilic drug methotrexate (MTX), with sustained release. Antisolvent nanoprecipitation technique was employed for the formulation of nanoparticles (NPs). Optimized formulation depicted 209.6 ± 31.3 nm particle size, 0.209 ± 0.072 PDI and 14.98 ± 1.33 %w/w drug loading. In vitro release depicted biphasic release for 12 h with initial burst phase followed by sustained release phase. In vitro Haemolytic study on RBCs revealed haemocompatible nature of MTX-Biosurfactant NPs compared to Biotrexate® (Zydus). In vitro cell culture studies showed 3.33 folds and 3.50 folds increase in cellular uptake of MTX at 10 µg/ml and 15 µg/ml concentration respectively for developed nanoparticles with 4.16 folds decrease in IC50 value. Higher apoptosis and increased lysosomal membrane permeability were obtained in MTX-Biosurfactants NPs. AUC and T1/2 was found to increase by 2.55 and 3.25 folds respectively in pharmacokinetic study. Significant reduction in tumor burden and serum toxicity marker level depicted efficacy and safety respectively of the formulation as compared to Biotrexate®. RBCs morphology was retained after MTX-Biosurfactants NPs exposure proving its haemocompatibility in vivo.

Naringin protects against cyclophosphamide-induced hepatotoxicity and nephrotoxicity through modulation of oxidative stress, inflammation, apoptosis, autophagy, and DNA damage.

Cyclophosphamide (CP) is a common chemotherapeutic agent that is effective against a wide variety of tumors. The associated hepatotoxicity and nephrotoxicity, however, limit its therapeutic use. Naringin (NG) is a natural flavanone glycoside that has pharmacological and therapeutic activities, such as anti-inflammation, anti-apoptotic, and antioxidant properties. Therefore, the present study was undertaken to evaluate the protective effect of NG against CP-induced hepatotoxicity and nephrotoxicity in rats. Rats were pre-treated with NG (50 and 100mg/kg b.w.) for 7days before administering a single dose of CP (200mg/kg b.w.) on the seventh day. CP-induced hepatotoxicity and nephrotoxicity were associated with an increase in serum toxicity markers and a decrease in antioxidant enzyme activities. CP also induced inflammatory responses by increasing the levels of tumor necrosis factor-α (TNF-α), nuclear factor kappa B (NF-κB), interleukin-6 (IL-6), and interleukin-1β (IL-1β), and activities of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Moreover, it activated the apoptotic and autophagic pathway by increasing cysteine aspartate-specific protease-3 (caspase-3) expression and light chain 3B (LC3B) level and also increased the expression of 8-hydroxy-2'-deoxyguanosine (8-OHdG), which is the marker of oxidative DNA damage. Pre-treatment with NG (50 and 100mg/kg), however, significantly decreased serum toxicity markers, increased antioxidant enzyme activities, and regulated inflammation, apoptosis, autophagy, and oxidative DNA damage in hepatic and renal tissues. These results indicated that NG was an effective protectant against CP-induced hepatotoxicity and nephrotoxicity.

Chemoprotective effects of curcumin on doxorubicin-induced nephrotoxicity in wistar rats: by modulating inflammatory cytokines, apoptosis, oxidative stress and oxidative DNA damage

Doxorubicin (DXR) is one of the most important chemotherapeutic agent. However, nephrotoxicity reduces its clinical utility in humans. The aim of the study was to investigate protective effects of curcumin (CMN) against DXR-induced nephrotoxicity. Rats were subjected to oral treatment of CMN (100 and 200 mg/kg body weight) for 7 days. Nephrotoxicity was induced by single intra peritoneal injection of DXR (40 mg/kg body weight) on the fifth day and then the experiment was terminated on the eighth day. Nephroprotective effects of CMN were associated with decrease in serum toxicity markers and increase in antioxidant enzyme activities. CMN was able to reduced the levels of inflammatory markers such as TNF-α, NF-κB, IL-1β, iNOS and COX-2 in the rats. It also reduced the expressions of apoptotic marker including caspase-3, and oxidative DNA damage marker including 8-OHdG. Collectively, these findings indicated that CMN protect against DXR-induced nephrotoxicity.

EXPLORATION OF GOITROGENIC/ANTITHYROIDAL POTENTIALITY OF BAMBOO-SHOOTS IN RELATION TO THIOUREA

Objective: Natural goitrogens present in plant foods or antithyroidal drugs both alter the morphology and normal functional status of the thyroid gland interfering the synthesis and secretion of thyroid hormones. In this study, the goitrogenic potential of bamboo shoots (BS) containing natural goitrogens has been compared against a potent synthetic antithyroidal drug thiourea.Methods: BS was fed to 6 rats by 1/3rdreplacement of 180grams (g) of their food i.e.60g of BS containing 35g of goitrogens of cyanogenic origin such that each rat ideally consumed 6 mg/100g of body weight per day and thiourea at a near equal dose of 6 mg/100g of body weight per day was force fed to another 6 rats for a period of 45 d. Changes in food consumption pattern, serum toxicity marker SGOT and SGPT, morphological changes like thyroid gland weight and histology and functional aspects like TPO activity, Na+-K+ATPase activity, urinary iodine excretion and serum T3,T4 and TSH levels induced by this natural and synthetic agent respectively were investigated. Results analyzed by ANOVA followed by post hoc tests.Results: Food consumption pattern was similar in all groups while serum toxicity markers SGOT, SGPT showed a non-significant increase in experimental groups. Increase in body and thyroid gland weight as compared to control was seen on treatment with both antithyroidal agents, a greater percentage of increase was seen in thiourea treated group. TPO activity, Na+-K+ATPase activity, serum T3 and T4levels were decreased significantly in both treated groups as compared to normal, with maximum inhibition in the thiourea treated group. Histological plates of BS treated thyroid revealed hypertrophy and thyroid follicular cell disruption with microcytic infiltration. Thiourea treated gland histological plate revealed complete abolition of normal histoarchitecture with marked changes in colloidal area and hyperplasia with folding and papillae on the epithelium.Conclusion: In overall, the data indicate that though the goitrogenic potentiality of BS cannot be considered having similar efficacy to that of thiourea but as a food entity by itself, it has potent antithyroidal activity even in presence of adequate iodine intake.